Document Detail


Tacrine-NO donor and tacrine-ferulic acid hybrid molecules as new anti-Alzheimer agents: hepatotoxicity and influence on the cytochrome P450 system in comparison to tacrine.
MedLine Citation:
PMID:  20533758     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Tacrine (CAS 321-64-2) is a reversible acetylcholine esterase inhibitor that, despite exerting beneficial effects on Alzheimer's disease (AD), displays marked hepatotoxicity. Searching for safer drugs and taking into account the multi-pathogenesis of AD, two tacrine-NO donor hybrid molecules (FL16, FL38) as well as a tacrine-ferulic acid hybrid (FL67) were synthesized. NO donors coupled to the tacrine moiety may exert an additional beneficial effect on AD via an increased blood supply to the brain and by reducing inflammation. Ferulic acid is an antioxidant. To investigate the hepatotoxicity and effects on the cytochrome P450 (CYP) system of the liver, female rats were treated with the highest tolerated dose of tacrine or equimolar doses of the novel compounds 24 or 36 h, respectively, before sacrifice. Tacrine caused pericentral necrosis and fatty degeneration of the hepatocytes, loss of liver glycogen and (indicating oxidative stress) induction of heme oxygenase (HO)-1. No histopathological changes were observed with the hybrids, but a glycogen deficit and an elevation of HO-1 was noticed after FL38 or FL67 treatment. Both tacrine and the hybrids, but mainly FL38 and FL67, caused an induction of CYP1A1, 2B1 and 3A2 expression. CYP activity was noticeably increased after treatment with FL38 and FL67 only. Thus, since it displays much less hepatotoxicity and interaction potential at the CYP system than tacrine and the other hybrids, FL16 is a good candidate for further investigations.
Authors:
Amelie Lupp; Dorothea Appenroth; Lei Fang; Michael Decker; Jochen Lehmann; Christian Fleck
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Arzneimittel-Forschung     Volume:  60     ISSN:  0004-4172     ISO Abbreviation:  Arzneimittelforschung     Publication Date:  2010  
Date Detail:
Created Date:  2010-06-10     Completed Date:  2010-07-12     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0372660     Medline TA:  Arzneimittelforschung     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  229-37     Citation Subset:  IM    
Affiliation:
Institute of Pharmacology and Toxicology, Friedrich Schiller University, Jena, Germany. Amelie.Lupp@mti.uni-jena.de
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MeSH Terms
Descriptor/Qualifier:
Alzheimer Disease / drug therapy*
Animals
Coumaric Acids / therapeutic use*,  toxicity
Cytochrome P-450 Enzyme System / metabolism*
Drug-Induced Liver Injury / enzymology,  pathology*
Female
Glutathione / metabolism
Heme Oxygenase-1 / biosynthesis
Lipid Peroxidation / drug effects
Liver / enzymology,  pathology
Liver Glycogen / metabolism
Nitric Oxide Donors / therapeutic use*,  toxicity
Nootropic Agents / chemistry*,  therapeutic use*,  toxicity
Oxidative Stress / drug effects
Rats
Rats, Wistar
Tacrine / chemistry*,  therapeutic use*,  toxicity
Chemical
Reg. No./Substance:
0/Coumaric Acids; 0/Liver Glycogen; 0/Nitric Oxide Donors; 0/Nootropic Agents; 1135-24-6/ferulic acid; 321-64-2/Tacrine; 70-18-8/Glutathione; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.14.99.3/Heme Oxygenase-1

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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